Tatsushi Tomomitsu

Therapeutic effects of alendronate 35 mg once weekly and 5 mg once daily in Japanese patients with osteoporosis: a double-blind, randomized study

The efficacy and safety of treatment with oral alendronate (ALN) 35u2009mg once weekly for 52 weeks were compared with those of ALN 5u2009mg once daily in a double-blind, randomized, multicenter study of Japanese patients with involutional osteoporosis. The primary efficacy end point was the percent change from baseline in the lumbar spine (L1–L4) bone mineral density (BMD) after 52 weeks of treatment. In this study, 328 patients were randomized to ALN 5u2009mg once daily (160 patients) or ALN 35u2009mg once weekly (168 patients). The adjusted mean percent change from baseline in lumbar spine (L1–L4) BMD after 52 weeks of treatment was 5.8% and 6.4% in the once-daily group and the once-weekly group, respectively (both P < 0.001). The 95% confidence interval for the difference in spine BMD change between the two treatment groups was −0.31% to 1.48%, indicating that the two regimens were therapeutically equivalent, since the confidence interval fell entirely within the predefined equivalence criterion (±1.5%). The time course of the spine BMD increase was also similar for both regimens. Regarding total hip BMD, mean changes from baseline at 52 weeks were 2.8% and 3.0% in the once-daily group and the once-weekly group, respectively. In addition, the bone markers (urinary deoxypyridinoline, urinary type-I collagen N-telopeptides, and serum bone-specific alkaline phosphatase) were reduced to a similar level by either treatment throughout the treatment period. The tolerability and safety profiles were also similar between the treatment groups. Taken together, we conclude that the efficacy and safety of the ALN 35-mg once-weekly regimen are therapeutically equivalent to those of the ALN 5-mg once-daily regimen.

Biochemical markers for the detection of bone metastasis in patients with prostate cancer : diagnostic efficacy and the effect of hormonal therapy

Abstract In the present study, we investigated the diagnostic effectiveness of biochemical markers of bone turnover for the detection of bone metastasis from prostate cancer and changes in the levels of these markers caused by hormonal therapy. Ninety-five patients with prostate cancer were divided into one of three groups: 26 patients with bone metastasis (BM(+)), 35 patients without bone metastasis on nonhormonal therapy (BM(−)HT(−)) and 34 patients without bone metastasis on hormonal therapy (BM(−)HT(+)). All patients in the BM(+) group had received hormonal therapy. Serum or urinary levels of the following biochemical markers of bone turnover were examined: bone-specific alkaline phosphatase (B-ALP), osteocalcin (OC), type I procollagen C-propeptide (PICP), type I collagen cross-linked C-telopeptide (ICTP), C-telopeptide fragment (CTx), N-telopeptide fragment (NTx), total pyridinoline (T-Pyr), total deoxypyridinoline (T-D-Pyr) and free deoxypyridinoline (F-D-Pyr). The BM(+) group showed significantly higher values than the BM(-)HT(-) group for B-ALP, PICP, NTx, CTx, T-Pyr, T-D-Pyr, and F-D-Pyr. Compared with the BM(−)HT(+) group, the BM(+) group showed significantly higher values for B-ALP, ICTP, NTx, T-Pyr and T-D-Pyr. The levels of B-ALP, NTx, CTx, T-D-Pyr and F-D-Pyr were significantly different between the BM(−)HT(−) and BM(−)HT(+) groups. All markers, except OC and CTx, significantly were correlated with the extent of bone metastasis on bone scintigraphy. Of all markers, receiver operating characteristic (ROC) analyses revealed B-ALP and F-D-Pyr to be the most sensitive and specific for differentiation between the BM(+) and BM(−)HT(−) groups with regard to bone formation and resorption, respectively. In contrast, B-ALP and ICTP were most sensitive and specific for differentiation between the BM(+) and BM(−)HT(+) groups. The results suggest that hormonal therapy greatly affects the efficacy of PICP, CTx and F-D-Pyr in the diagnosis of bone metastasis, whereas its effects on ICTP are small. Although bone metabolic markers would be useful in the diagnosis of bone metastasis from prostate cancer, the effects of hormonal therapy on bone metabolism should be kept in mind in their evaluation.

Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis—a double-blind, randomized, dose-finding study

SummaryThe efficacy and safety of oral placebo or odanacatib 10, 25, or 50 mg once weekly for 52 weeks were evaluated in a double-blind, randomized, multi-center study in Japanese female and male patients with osteoporosis.IntroductionOdanacatib is a selective and reversible cathepsin K inhibitor that decreases bone resorption and increases bone mineral density (BMD).MethodsThe primary efficacy endpoint was percent change from baseline to weekxa052 in lumbar spine BMD. Secondary endpoints included percent change in total hip, femoral neck, and trochanter BMD and in bone biomarkers after treatment for 52xa0weeks.ResultsIn this study, 286 patients [94xa0% female, mean age (SD) 68.2 (7.1) years] were included in the analysis. The least-squares mean percent changes from baseline to weekxa052 in the groups receiving placebo, 10, 25 and 50xa0mg of odanacatib for lumbar spine (L1∼L4) BMD were 0.5, 4.1, 5.7, and 5.9xa0% and for total hip BMD were −0.4, 1.3, 1.8, and 2.7xa0%, respectively. The changes in femoral neck and trochanter BMD were similar to those at the total hip. Bone turnover markers were reduced in a dose-dependent manner. However, the effects of odanacatib on bone formation markers were less compared with the effects on bone resorption markers. Tolerability and safety profiles were similar among all treatment groups with no dose-related trends in any adverse events.ConclusionsWeekly odanacatib treatment for 52xa0weeks increased BMD at the lumbar spine and at all hip sites in a dose-dependent manner and was well tolerated in Japanese patients with osteoporosis.

AGE-RELATED CHANGES IN VERTEBRAL HEIGHT RATIOS AND VERTEBRAL FRACTURE

Because no gold standard for the definition of vertebral fracture exists, there has been controversy about whether mild vertebral deformities are truly fractures or simply normal variation in vertebral size and shape. The aim of this study was to assess the associations of mild variations of vertebral height ratios to definite vertebral fractures. In 479 Japanese women (age 53.9±9.1 years) who visited our institute for a medical checkup, we performed lateral lumbar radiographs and morphometric parameters were derived by measuring the anterior (Ha), middle (Hm) and posterior (Hp) height of each vertebral body from T12 to L4. Vertebral height ratios, Ha/Hp, Hm/Hp or Hp/Hp′ of adjacent vertebrae that were more than 3 SD different from vertebra-specific means of normative data were considered to indicate fractures. Forty-five women were diagnosed with at least one fracture. After excluding the subjects with vertebral fracture, we examined the associations of the variations in vertebral height ratios with age, anthropometric parameters and lumbar bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. Vertebral height ratios, especially Hm/Hp in postmenopausal women, tended to decrease with age and were positively associated with BMD. No significant correlation was observed between anthropometric parameters and vertebral height ratios. Age-related decrease in vertebral height ratios (Ha/Hp and Hm/Hp, each averaged from T12 to L4) was significant even after the correction for BMD. Mean values of height ratios of non-fractured vertebrae adjusted for age and BMD were significantly lower in postmenopausal women with vertebral fracture than in those without vertebral fracture. Logistic regression analysis showed that BMD and height ratios of non-fractured vertebrae were independent predictors of vertebral fracture risk. The results suggest that older women, and women with at least one obvious (3 SD) fracture, tend to have mild deformities which do not qualify using the 3 SD definition. These mild deformities may represent real consequences of osteoporosis, because they are more pronounced among women with obvious fracture.

Calcaneus as a Site for the Assessment of Bone Mass

The calcaneus is a skeletal site frequently used for monitoring bone loss after spaceflight, because it is sensitive to microgravity-induced bone mineral loss and reflects the degree of demineralization in the vertebra and the femoral neck. In this article, methods for assessing the calcaneus are reviewed, and their potential applications and limitations as the monitoring site for bone loss in weightlessness are discussed. Currently, single or dual energy X-ray absorptiometry appears to be most sensitive for monitoring bone mineral loss in weightlessness. The results of recent studies suggest two- to threefold longer follow-up times required for ultrasound techniques. However, ultrasound devices can be designed to be portable, making them attractive for inflight use, and ultrasound techniques are expected to provide information related to bone quality. Additional investigations that assess new ultrasound techniques would be important to determine and utilize the full potential of this technology for monitoring bone loss in weightlessness.

The usefulness of bone-marrow scintigraphy in the detection of bone metastasis from prostatic cancer.

We used a combination of bone and bone-marrow scintigraphy to study 25 patients with prostatic cancer. Of the 18 cases whose 99mTc-methylene diphosphonate (MDP) bone scans showed hot spots in the lower lumbar region of the spine and/or the pelvic bone, 8 had normal bone-marrow scintigrams. These 8 patients were subsequently shown to have senile, degenerative changes of the spine. On the other hand, in 9 of the 10 patients whose bone-marrow scintigrams showed accumulation defects, follow-up study and characteristic X-ray findings confirmed the presence of metastases. In all 6 cases with extensive bone metastases shown by 99mTc-MDP bone scintigraphy, 99mTc-sulphur-colloid bone-marrow scintigraphy showed multiple accumulation defects. In conclusion, bone-marrow scintigraphy was found to be useful in distinguishing metastatic lesions from benign degenerative changes in the cases with suspected bone involvement, as well as in evaluating equivocal lesions in the pelvis.We used a combination of bone and bone-marrow scintigraphy to study 25 patients with prostatic cancer. Of the 18 cases whose 99mTc-methylene diphosphonate (MDP) bone scans showed hot spots in the lower lumbar region of the spine and/or the pelvic bone, 8 had normal bone-marrow scintigrams. These 8 patients were subsequently shown to have senile, degenerative changes of the spine. On the other hand, in 9 of the 10 patients whose bone-marrow scintigrams showed accumulation defects, follow-up study and characteristic X-ray findings confirmed the presence of metastases. In all 6 cases with extensive bone metastases shown by 99mTc-MDP bone scintigraphy, 99mTc-sulphur-colloid bone-marrow scintigraphy showed multiple accumulation defects. In conclusion, bone-marrow scintigraphy was found to be useful in distinguishing metastatic lesions from benign degenerative changes in the cases with suspected bone involvement, as well as in evaluating equivocal lesions in the pelvis.

Measurement of regional cerebral blood flow with123I-IMP using one-point venous blood sampling and causality analysis: Evaluation by comparison with conventional continuous arterial blood sampling

ObjectiveArterial input function represents the delivery of intravascular tracer to the brain. The optimal setting of this function is essential for measuring regional cerebral blood flow (rCBF) based on the microsphere model usingN-isopropyl-4-[123I]iodoamphetamine (123I-IMP), in which the arterial123I-IMP concentration (integral value) during the initial 5 min is usually applied. We developed a novel method in which the arterial123I-IMP concentration is estimated from that in venous blood samples.MethodsBrain perfusion SPECT with123I-IMP was performed in 110 patients with disorders of the central nervous system. A causality analysis determined the relationship between various SPECT parameters and the ratio of the octanol-extracted arterial radioactivity concentration during the first 5 min (Caoct) to the octanol-extracted venous radioactivity concentration at 27 min after an intravenous injection of123I-IMP (Cvoct). The Caoct/Cvoct value was estimated using various SPECT parameters and compared with the directly measured value.ResultsThe measured and estimated values of Caoct/ Cvoct (r = 0.856, n = 50) closely correlated when the following 7 parameters were included in the regression formula: radioactivity concentration in venous blood sampled at 27 min (Cv), Cvoct, Cvoct/Cv, and 4 parameters related to cerebral tissue accumulation that were measured using a four-head gamma camera 5 and 28 min after123I-IMP injection. Furthermore, the rCBF values obtained using the input function estimated by this method also closely correlated with the rCBF values measured using the continuous arterial blood sampling (r = 0.912, n = 180).ConclusionThese results suggest that this method would serve as a convenient and less invasive method of rCBF measurement in the clinical setting.

Bone mineral measurement in Japan.

Various methods for evaluating bone mineral in appendicular, and axial bone or in the whole skeleton have recently become available. As bone mineral is one of the major determinants of bone strength, its exact measurement should be useful for the diagnosis of osteoporosis, as well as for the prediction of fracture risk and monitoring of therapeutical response.The aims of this paper are to review the fundamental performance of bone mineral measurements, the improvements in DXA systems, and the progress in site-specific bone mineral instruments for the radius and calcaneus used in Japan, and to introduce diagnostic criteria for primary osteoporosis, and report on annual rates of bone loss in Japanese females.

Accumulation of99mTc-HM-PAO in photon deficient areas in bone scan of bone metastasis from hepatocellular carcinoma

To evaluate bone metastasis from hepatocellular carcinoma (HCC), both bone and99mTc-HM-PAO scintigraphies were performed in six patients with clinically and pathologically confirmed HCC. Two patients had a bone scintigram which revealed abnormal accumulation in the skull base, pelvic bone and thoracic spine. The99mTc-HM-PAO scans of both these patients also showed abnormal accumulation in the same sites. The bone scintigrams in one patient revealed not only abnormal accumulation in the ribs but also photon deficient areas in the sternum, thoracic spine and femur, while99mTc-HM-PAO scans showed abnormal accumulation in all these sites. In three patients, bone scintigraphy revealed photon deficient areas in the ribs, pelvic bone and femur, and their99mTc-HM-PAO scintigrams showed abnormal accumulation in the same sites. Thus, it was shown that, in the detection of bone metastasis from HCC by means of bone scintigraphy, it was necessary to pay attention to hot and cold lesions, and that a combination study with99mTc-phosphorous compounds and99mTc-HM-PAO was useful in evaluating these lesions.

Lateral scanning of the lumbar spine: Bone mineral density determination with dual energy X-ray absorptiometry

In order to exclude the metabolically less-active cortical bone in the posterior portion of the lumbar spine, and to exclude the calcification of abdominal aorta which frepuently occurs in elderly persons, both of which are included in the conventional anteroposterior (AP) bone mineral determinations, clinical interest has been directed toward lateral scanning. In this paper, the performance and clinical application of lateral scanning with dual energy X-ray absorptiometry (DEXA) have been reviewed.The precision, estimated as the reproducibility of measurements, of lateral bone mineral density (BMD), is inferior to that of AP-BMD (N=5, C.V. 5.57% vs 1.80%). With lateral scanning, the distributions of bone mineral within the vertebral body was different. The highest BMD was observed in the posterior inferior portion (100%), followed by the posterior superior (89%), anterior inferior (77%), and anterior superior portions (65%). In lateral scans, BMD within the region of interest (ROI) containing the shell, composed of cortical bone, is higher than BMD within the ROI without the shell (N=28, 87.8±5.9% for shell (+) vs 81.5±10.3% for shell (−), p<0.01, when AP-BMD in L3 is defined as 100%). Age-related bone loss in males was recognized from lateral BMD measurements (r=−0.342, p<0.01), while no significant correlation was recognized between age and AP-BMD.In conclusion, although lateral scanning needs further improvement in precision, lateral scanning of the lumbar spine with DEXA will provide more informations in evaluating age-related bone loss.